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15 February 2014, Volume 23 Issue 2

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Journal of Chinese Pharmaceutical Sciences

2014, 23(2):  71-74. 

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Original articles

Population pharmacokinetics of risperidone based on meta-analysis and its application in therapeutic drug monitoring of Chinese schizophrenic patients

Shuangmin Ji, Dewei Shang, Xipei Wang, Anning Li, Yupeng Ren, Liang Li, Tianyan Zhou, Chuanyue Wang, Wei Lu

2014, 23(2):  75-82.  DOI: 10.5246/jcps.2014.02.009

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Population pharmacokinetic meta-analysis method was used in order to obtain the pharmacokinetic characteristics of risperidone and its active metabolite. Eighteen studies were selected from published papers from 1995 to 2011. A model consisted of two compartments for parent drug and one compartment for its active metabolite combined with a flexible absorption process was developed based on the meta-dataset. The population-predicted apparent clearance for risperidone and 9-hydroxyrisperidone, the active metabolite was 7.66 L/h and 7.38 L/h, and the apparent volume of distribution in the central compartment was 70.6 L and 117 L, respectively. The final model was evaluated by visual predictive check (VPC) based on 1000 times model simulation. This model was adequately used to predict clinical therapeutic drug monitoring (TDM) data from 42 Chinese inpatients. Bias (mean prediction errors, MPE) and precision (root mean squared prediction errors, RMSE) were calculated to statistically analysis the population prediction error. It was demonstrated that the model developed from the meta-dataset was reliable and can be used to facilitate the individualized treatment for a target population.



A study of liposomal doxorubicin modified by tumor metastasis targeting peptide for its specificity to highly metastatic breast cancer cells

Fang Yang, Bing He, Wenbing Dai, Xueqing Wang, Jiancheng Wang, Xuan Zhang, Qiang Zhang

2014, 23(2):  83-88.  DOI: 10.5246/jcps.2014.02.010

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Tumor metastasis emerges as a crucial target for tumor therapy. In this study, a tumor metastasis targeting peptide (TMT) was conjugated to a lipid material (PEG-DSPE) to obtain the targeting compound (TMT-PEG-DSPE), which was used to construct the targeted liposomal doxorubicin (TMT-LS-DOX). We showed that TMT-LS-DOX presented satisfactory pharmaceutical characteristics. This metastasis-specific delivery system was tested in two highly metastatic breast cancer cell lines (MDA-MB-435S and MDA-MB-231) with a non-metastatic breast cancer cell line (MCF-7) as the control. The free TMT peptide itself showed no cytotoxicity even at the concentration of 100 μg/mL. Importantly, the enhanced cellular uptake of TMT-LS-DOX to both MDA-MB-435S and MDA-MB-231 cell lines was demonstrated as compared to MCF-7 cells, via a TMT-mediated mechanism demonstrated by a receptor competition study. In conclusion, the TMT modified nanocarriers might provide a strategy to enhance the specificity of chemotherapeutic agents to highly metastatic breast cancer.



Optimization and characterization of nimesulide bilayer tablets by response surface methodology

Li Shan, Yunzhou Fan, Yuli Wang, Hongge Chen, Chunsheng Gao, Meiyan Yang

2014, 23(2):  89-93.  DOI: 10.5246/jcps.2014.02.011

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The objectives of this present investigation were to develop and formulate nimesulide bilayer tablets by using different polymer combinations and fillers, to optimize the formulations for different drug release variables by orthogonal design and central composite design-surface methodology and to evaluate drug release pattern of the optimized product. The bilayer tablet containing a fast release layer (FRL) and a sustained release layer (SRL) provided an initial burst release of nimesulide, followed by the sustained release for a period of time. The optimal formulation obtained was as follows: (I) the formulation of FRL: nimesulide, 50 mg; lactose, 92 mg; starch, 22 mg; CCMC-Na, 14 mg; PVP K30, 1 mg; micronized silica gel, 1 mg; magnesium stearate, 0.9 mg; and iron oxide red, 0.1 mg; and (II) the formulation of SRL: nimesulide, 150 mg; HPMC K100LV, 26 mg; HPMC K4M, 33 mg; lactose, 54 mg; PVP K30, 1 mg; micronized silica gel, 1 mg; and magnesium stearate, 0.9 mg. According to the optimal formulation, the biphasic type of release was identified. The in vitro drug dissolution from the bilayer tablets was sustained for about 16 h after releasing 15% of drug in the first 10 min. The developed nimesulide bilayer tablets with improved efficacy can perform therapeutically better than the conventional tablets.



Chemical constituents from the flowers of Rhododendron molle G. Don

Xuan Wang, Yanwei Hu, Dan Yuan, Hongzheng Fu

2014, 23(2):  94-98.  DOI: 10.5246/jcps.2014.02.012

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The aim of current study was to investigate the chemical constituents from the flowers of Rhododendron molleG. Don. The isolation and purification of components were achieved by a series of chromatography including silica gel, Sephadex LH-20, and reversed-phase HPLC. Their structures were identified based on 1D, 2D NMR, and mass spectral analysis. Fifteen known compounds were isolated and their structures were identified as 2E,4Z-abscisic acid (1), 2α-hydroxy-oleanolic acid (2), oleanic acid (3), asiatic acid (4), benzyl glucoside (5), dibutyl phthalate (6), β-sitosterol (7), vitexin (8), quercetin (9), steraric acid (10), rhodomollein I (11), rhodojaponin VI (12), rhodomollein XI (13), rhodojaponin II (14), kalmanol (15). Compounds 1–10 were isolated from Rhododendron molle for the first time.



Flavonoids from Tibetan medicine Oxytropis falcate Bunge

Xiaojing Zhang, Lingyu Li, Kelsang Norbo, Shanshan Wang, Quesheng, Wei Cheng, Hong Liang, Yuying Zhao, Qingying Zhang

2014, 23(2):  99-105.  DOI: 10.5246/jcps.2014.02.013

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Twenty-seven flavonoids, including 10 isoflavones, 9 flavanones, 3 dihydrochalcones, 3 flavonols and 2 flavans, were isolated from the whole plant of Tibetan medicine Oxytropis falcate Bunge. Structure elucidation was conducted by extensive spectroscopic analysis, including MS, NMR and CD spectra. Twelve compounds were obtained from this plant for the first time, among which 10 compounds were obtained from the genus of Oxytropis for the first time.



Combination of reversed phase liquid chromatography and zwitterion exchange-reversed phase-hydrophilic interaction mixed-mode liquid chromatography coupled with mass spectrometry for the analysis of antibiotics and their impurities

Li Lu, Jin Li, Shaohong Jin, Changqin Hu

2014, 23(2):  106-117.  DOI: 10.5246/jcps.2014.02.014

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In this study, a system involving two-dimensional, column-switching high-performance liquid chromatography (HPLC) coupled with tandem mass spectrometry (LC-MS/MS) was developed and optimized for the analysis of antibiotics and their related substances. In the first-dimensional chromatography, the analytes were separated on a zwitterion exchange-reversed phase-hydrophilic interaction (ZIC-RP-HILIC) mixed-mode column coupled with tandem mass spectrometry (LC-MS/MS). A commonly used reversed phase LC column was employed in the second-dimensional chromatography. The mobile phase for the ZIC-RP-HILIC mixed-mode chromatography consisted of a volatile buffer that was compatible with LC-MS/MS, which enhanced the efficiency of ionization for structure elucidation. The antibiotic impurities eluted in the ion-pairing reversed phase chromatography were directly characterized by the ZIC-RP-HILIC-MS system, and the orthogonal separation of ZIC-RP-HILIC mixed-mode chromatography and reversed phase LC provided extra confidence that no impurity was missed. The efficiency of this method was demonstrated in the analysis of penicillin V potassium, oxacillin sodium, ceftriaxone sodium, and their impurities. In addition, this method is convenient for impurity profiling of antibiotics, and may be used for the analysis of other pharmaceutical ingredients.



A validated HPLC method for the determination of donepezil in human plasma after derivatization with 9-fluorenylmethyl chloroformate

Reza Ahmadkhaniha, Abdolrahman Nazari, Mohsen Amini, Effat Souri

2014, 23(2):  118-123.  DOI: 10.5246/jcps.2014.02.015

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A new HPLC method has been developed for determining donepezil in human plasma. To find the optimum conditions, a derivatization reaction was performed in different media, and the reaction product was identified by NMR and GC-MS after a semi-preparative HPLC separation. Under optimized conditions, donepezil was derivatized by 9-fluorenylmethyl chloroformate in chloroform and carbonate buffer at pH 9.5 in the presence of NaI after solid-phase extraction from a plasma sample. The reaction product was quantified on a reversed-phase TRACER EXCEL ODS-A, 5 µm column using a mixture of acetonitrile–10 mM acetate buffer (pH 6.0)–THF (60:35:5, v/v/v) as the mobile phase with fluorescence detection at 264 nm (ex) and 313 nm (em). Fluoxetine was used as the internal standard. The total run-time of the analysis was about 10 min, and a clean chromatogram was obtained. The developed method was linear over the range of 1–100 ng/mL in 500 µL of plasma samples (r²>0.998). The intra-day and inter-day precision values were in the range of 2.6%–11.6%. The limit of quantification was 1 ng/mL.



Sex differences in morphine dependence and plasma levels of morphine and morphine-3-glucuronide in rats

Li Sun, Ruiying He, Xiaoxiao Li, Lijing Liu, Yanping Den

2014, 23(2):  124-131.  DOI: 10.5246/jcps.2014.02.016

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To examine whether there are sex differences in morphine dependence and its metabolism. Naloxone-precipitated withdrawal study was performed. Twenty rats were induced by naloxone 1 h after a single dose of morphine injection. The withdrawal syndromes were recorded and an HPLC-UV method was set up to quantify the plasma levels of morphine and morphine-3-glucuronide (M3G). In the spontaneous withdrawal study, 97 rats were treated with progressive morphine for 28 d to develop physical dependence. The spontaneous withdrawal syndromes were recorded and plasma levels of morphine and M3G were determined after the last injection. No significant differences were observed in withdrawal syndrome of naloxone precipitating. More severe spontaneous withdrawal syndromes were produced by chronic morphine injection in male rats than in female rats (P<0.05). Higher maximum plasma concentration (C_max) of morphine was measured in male rats than female rats, while female rats had higher C_max of M3G than male rats in both acute and chronic morphine administration. Our results indicated that sex differences existed in withdrawal syndrome of morphine-dependent rats, and the pharmacokinetics of morphine showed sex difference by both acute and chronic administration. There might be a relationship between the severity of withdrawal syndrome and the plasma concentrations of morphine, M3G, and the ratio of morphine to M3G (M3G/MOR).



Management of acute diarrhea in adults in hospitals in Beijing did not adhere well to Manatsathit working party guidelines

Fengqin Hou, Yan Wang, Jun Li, Ying Liu, Guiqiang Wang

2014, 23(2):  132-137.  DOI: 10.5246/jcps.2014.02.017

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How hospital physicians adhere to guidelines on management of diarrhea in adults has not been adequately assessed. The purposes of this study were to evaluate the management of acute diarrhea in adults and to assess the adherence of hospital physicians to the Manatsathit working party recommended guidelines.A cross sectional survey was carried out during May to July 2011 among physicians in 10 hospitals in Beijing, China.Data were collected for 400 patients (208 females and 192 males) with the mean age of (35.5±14.8) years. Overall, 357 (89.3%) patients presented with watery diarrhea and 43 (10.7%) patients presented with bloody diarrhea. Of 357 patients who needed fluid and electrolyte therapy, however, up to 114 (31.9%) patients were not ordered any fluid and electrolyte replacement; although only 28 (7.8%) actually supposed to use the antibiotics due to an age of higher than 65 years or being immunologically compromised, however, 186 (52.1%) were prescribed antibiotics which significantly deviated from the guidelines recommended by the Manatsathit working party. Antimotility drugs were only used in seven patients with watery diarrhea, which was in line with the guidelines. Hospital physicians in Beijing did not adhere well to the guidelines for the management of acute diarrhea. Physicians might need to be refreshed on the guidelines in this specific field.



Other

The 4th editorial board meeting of Journal of Chinese Pharmaceutical Sciences was held in Peking University Health Science Center

Journal of Chinese Pharmaceutical Sciences

2014, 23(2):  138-140. 

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The 4^th editorial board meeting of Journal of Chinese Pharmaceutical Sciences (JCPS) was held in Peking University Health Science Center (PUHSC) on January 13, 2014. The meeting was presided by Prof. Demin Zhou, the Executive Editor-in-chief of JCPS. Academician Lihe Zhang, the Editor-in-chief, gave the opening speech. Xingping Liu, vice minister of China Association for Science and Technology (CAST), Prof. Luqi Huang, vice president of Chinese Pharmaceutical Association (CPA), Prof. Weigang Fang, Deputy Director of PUHSC, Prof. Junyi Liu, Dean of School of Pharmaceutical Sciences, Peking University, and other university professors and scholars attended the meeting.

Prof. Heqing Huang, Executive Associate Editor-in-chief of JCPS, delivered a speech on behalf of the Editorial Office of JCPS. She pointed out that JCPS is playing a critical role in the communication of new discoveries in drug development to the scientific community. To fulfill the roles as an internationally recognized platform for the display of the new drug discoveries supported by the National New Drug Innovation programs, the JCPS editorial office will take advantage of its English language specialty, emphasize quality and digital access, and promote the advancement of the journal. On the basis of her speech, editors discussed and analyzed the current problems and formulated an outline for the advancement of JCPS.
    In the afternoon, Prof. Hualiang Jiang, the Associate Editor-in-chief of Journal of Medicinal Chemistry (JMC) and Prof. Dean Guo gave speech on the development of scientific journals. And Prof. Shilin Chen, Prof. Fener Chen and Prof. Suodi Zhai spoke on the progress of their scientific researches. At the end of the meeting, Academician Lihe Zhang met again withtheeditorial board. He hoped that we will strive to enhance the quality of JCPS, strengthen the international presence, play a stronger role as the expert committee.